Massive genome havoc in breast cancer is revealed

July 12, 2018, Cold Spring Harbor Laboratory
Long-read sequencing enabled the team to reconstruct in great detail the history of how the HER2 gene gets massively amplified in HER2-positive breast cancer cells, says Dr. Schatz. Top rectangle shows a 2 million base-pair segment of chromosome 17 occupied by the HER2 gene (also called ERBB2). A small segment of the gene, already massively amplified, breaks off and fuses with chromosome 8 (lower rectangle). On that chromosome, parts of the gene are copied as many as 1000 times, with various segments jumping around within the chromosome (green arcs). This shows why we want to identify HER2-positive patients as early as possible, to prevent the kind of chaos that we register here cumulatively, says Schatz. Credit: Schatz Lab, CSHL/JHU

In cancer cells, genetic errors wreak havoc. Misspelled genes, as well as structural variations—larger-scale rearrangements of DNA that can encompass large chunks of chromosomes—disturb carefully balanced mechanisms that have evolved to regulate cell growth. Genes that are normally silent are massively activated and mutant proteins are formed. These and other disruptions cause a plethora of problems that cause cells to grow without restraint, cancer's most infamous hallmark.

This week, scientists at Cold Spring Harbor Laboratory (CSHL) have published in Genome Research one of the most detailed maps ever made of structural variations in a cancer cell's . The map reveals about 20,000 structural variations, few of which have ever been noted due to technological limitations in a long-popular method of .

The team, led by sequencing experts Michael C. Schatz and W. Richard McCombie, read genomes of the cancer cells with so-called long-read sequencing technology. This technology reads much lengthier segments of DNA than older short-read technology. When the results are interpreted with two sophisticated software packages recently published by the team, two advantages are evident: long-read sequencing is richer in terms of both information and context. It can, for instance, make better sense of repetitive stretches of DNA letters—which pervade the genome—in part by seeing them within a physically larger context.

The team demonstrated the power of long-read technology by using it to read the genomes of cells derived from a cell line called SK-BR-3, an important model for with variations in a gene called HER2 (sometimes also called ERBB2). About 20% of breast cancers are "HER2-positive," meaning they overproduce the HER2 protein. These cancers tend to be among the most aggressive.

"Most of the 20,000 variants we identified in this cell line were missed by short-read sequencing," says Maria Nattestad, Ph.D., who performed the work with colleagues while still a member of the Schatz lab at CSHL and Johns Hopkins University. "Of particular interest, we found a highly complex set of DNA variations surrounding the HER2 gene."

In their analysis, the team combined the results of long-read sequencing with results of another kind of experiment that reads the messages, or transcripts, that are being generated by activated genes. This fuller picture yielded an extraordinarily detailed account of how structural variations disrupt the genome in cancer and sheds light on how rapidly evolve.

Schatz, Adjunct Associate Professor at CSHL and Bloomberg Distinguished Associate Professor at Johns Hopkins University, and McCombie, a CSHL Professor, say it is "essential to continue building a catalog of variant cell types using the best available technologies. Long-read sequencing is an invaluable tool to capture the complexity of structural variations, so we expect its widespread adoption for use in research and clinical practice, especially as sequencing costs further decline."

Explore further: Altered gene regulation is more widespread in cancer than expected

More information: Nattestad M et al, (2018) "Complex rearrangements and oncogene amplifications revealed by long-read DNA and RNA sequencing of a breast cancer cell line" Genome Research.

Related Stories

Altered gene regulation is more widespread in cancer than expected

July 10, 2018
A large-scale study provides new insights into the mechanisms that can lead to cancer. It can happen when genes mutate, but cancer also can occur when the genetic regions involved in regulating gene expression change. In ...

An error-eliminating fix overcomes big problem in '3rd-gen' genome sequencing

July 1, 2012
The next "next-gen" technology in genome sequencing has gotten a major boost.

Method to determine when cell has 'cashed' RNA 'checks' written by active genes

January 27, 2018
DNA has often been called "the book of life," but this popular phrase makes some biologists squirm a bit. True, DNA bears our genes, which spell out the instructions our cells use to make proteins—those workhorse molecules ...

New breast cancer targets

May 4, 2018
Genome-wide association studies (GWAS) have identified more than 150 genetic variations associated with increased risk for breast cancer. Most of these variants are not located in protein-coding gene regions but are assumed ...

Mathematical 'Gingko trees' reveal mutations in single cells that characterize diseases

September 7, 2015
Seemingly similar cells often have significantly different genomes. This is often true of cancer cells, for example, which may differ one from another even within a small tumor sample, as genetic mutations within the cells ...

Complete genome sequence can be ID'd from amniotic fluid

March 27, 2018
(HealthDay)—The complete genome sequence of fetuses can be elucidated from amniotic fluid, according to a study published online March 15 in Clinical Chemistry.

Recommended for you

Researchers identify a mechanism that fuels cancer cells' growth

November 14, 2018
Scientists at the UCLA Jonsson Comprehensive Cancer Center have identified sodium glucose transporter 2, or SGLT2, as a mechanism that lung cancer cells can utilize to obtain glucose, which is key to their survival and promotes ...

A new approach to detecting cancer earlier from blood tests: study

November 14, 2018
Cancer scientists led by principal investigator Dr. Daniel De Carvalho at Princess Margaret Cancer Centre have combined "liquid biopsy", epigenetic alterations and machine learning to develop a blood test to detect and classify ...

New antibody breakthrough to lead the fight against cancer

November 14, 2018
Scientists at the University of Southampton have developed a new antibody that could hold the key to unlocking cancer's defence against the body's immune system.

Photoacoustic imaging may help doctors detect ovarian tumors earlier

November 14, 2018
Ovarian cancer claims the lives of more than 14,000 in the U.S. each year, ranking fifth among cancer deaths in women. A multidisciplinary team at Washington University in St. Louis has found an innovative way to use sound ...

Solving the mystery of NPM1 in acute myeloid leukemia

November 13, 2018
Although it has long been recognized that mutations of gene NPM1 play an important role in acute myeloid leukemia, no one has determined how the normal and the mutated forms of the protein NPM1 function.

Cognitive decline—radiation—brain tumor prevented by temporarily shutting down immune response

November 13, 2018
Treating brain tumors comes at a steep cost, especially for children. More than half of patients who endure radiation therapy for these tumors experience irreversible cognitive decline, a side-effect that has particularly ...

1 comment

Adjust slider to filter visible comments by rank

Display comments: newest first

Anonym518498
not rated yet Jul 12, 2018
does this spell therapeutic doom?

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.